The broad, long-term objective of this project is to explore the potential role of ethanol infusion in the vein of Marshall (VOM) in the treatment of atrial fibrillation (AF). AF is the most common sustained rhythm disorder in adults, affects more than 2.5 million Americans, and is associated with significant increases in stroke and mortality. Catheter ablation of AF, consists of pulmonary vein antral isolation (PVAI) and is the most powerful therapeutic strategy to treat AF, achieving normal rhythm in ~80% of patients. Important details of the mechanistic basis of PVAI, the optimal catheter technique, and the risk of complications are incomplete or controversial. The VOM is a left atrial vein branch of the coronary sinus that is the embryonic remnant of the left superior vena cava, and contains important sympathetic and parasympathetic nerves that have been implicated in the genesis of AF. Abnormal ectopic beats originating from the VOM have been shown to initiate AF. The VOM lies in a location in the LA that is normally part of the targeted tissue in PVAI and can be difficult to ablate conventionally due to its thickness (lateral ridge). Of note, it is also between the coronary sinus and the left pulmonary veins, an area commonly ablated to avoid left atrial flutter. It can also run close to the point of contact between the left atrium and the esophagus. A new technique to retrogradely cannulate the VOM was developed and validated in dogs and humans. Once cannulated, ethanol infusion achieves rapid tissue ablation without risk of collateral damage. The potential advantages include: ablation of sympathetic and parasympathetic innervation that promotes AF, ablation of VOM triggers for AF, ablation the lateral ridge from its epicardial side, and rapid tissue ablation from a right-sided procedure. We propose to study details of the mechanistic basis of this technique and to establish its role in the treatment of AF in humans. Specific aim #1 is to establish in dogs the electrophysiological effects of VOM ethanol infusion. We hypothesize that VOM ethanol infusion leads to marked direct and indirect electrophysiological changes in the LA that affect its ability to sustain AF. Direct effects would include of a new ethanol- ablated unexcitable LA area. Indirect effects would include abolition of vagal and sympathetic influences carried by the VOM. Experiments will be performed to delineate these effects. Specific aim #2 is to establish the role of VOM ethanol infusion as a useful adjunct to catheter ablation of AF in humans. Feasibility, safety, ablative effects and procedural impact of VOM ethanol infusion will be tested in patients subjected to conventional AF catheter ablation. Once the feasibility and safety are established, we will assess, in a randomized clinical trial, the value of adjunctive VOM ethanol infusion in de novo AF catheter ablation with PVAI, and in cases of recurrent AF after previous PVAI. PUBLIC HEALTH RELEVANCE: Atrial fibrillation is a significant health problem that causes stroke and increases death rates. Catheter ablation works in its treatment but can be improved. We have developed a new technique that is mechanistically sound and may improve catheter-based treatment of AF.